Oncogenes are genes that can cause cancer. Carcinogenesis can occur by a wide variety of mechanisms, including infection of cells by viruses containing oncogenes, activation of protooncogenes in the host genome, and mutations of protooncogenes and tumor suppressor genes. Carcinogenesis is fundamentally driven by somatic cell evolution (i.e. mutation and natural selection of variants with progressive loss of growth control). The genes that serve as targets for these somatic mutations are classified as either protooncogenes or tumor suppressor genes, depending on whether their mutant phenotypes are dominant or recessive, respectively.
The pattern of gene expression in a particular living cell is characteristic of its current state. Nearly all differences in the state or type of a cell are reflected in qualitative and quantitative differences in RNA levels of one or more genes. For example, oncogenes are positive regulators of tumorigenesis, while tumor suppressor genes are negative regulators of tumorigenesis. (Marshall, Cell, 64: 313-326 (1991); Weinberg, Science, 254: 1138-1146 (1991)).
Secreted proteins are involved in signaling between cells that are not in direct contact and play a role in differentiation of cells in mammals. The wnt gene family encodes a class of secreted proteins related to the Int1/Wnt1 protooncogene (Cadigan and Nusse, Genes & Development 11:3286-3305 (1997); U.S. Patent Publication 2004/0247593 A1, which is incorporated by reference). Dickkopf (Dkk) is a negative regulator of Wnt signaling (Glinka A, et al. Nature. 1998 Jan. 22; 391(6665):357-362; Niehrs C Trends Genet. 1999 August; 15(8):314-319). The Dkk protein is secreted and rich in cysteines. A family of human Dickkopf proteins (also referred to as “Cysteine-Rich Secreted Proteins” or CRSPs) have been reported. (see WO 00/52047 (McCarthy)). There are 4 Dkk members in the human genome with different activities. Some do not inhibit Wnt signaling (Wu W, et al. Cur Biol. 2000 Dec. 14-28; 10(24):1611-1614). There are presently no known non-vertebrate homologs of Dkk.
Additional members of the human Dickkopf gene family were identified by sequence homology. A Dkk-like protein referred to as Soggy-1 (referred to herein as wild-type DKKL-1 or DKKL-1 isoform 1) has been reported. (Krupnick V E, et al. Gene 238(2): 301-313 (1999); see WO 00/52047 (McCarthy)). The mouse ortholog of Soggy-1 has been reported. (Kaneko K J et al., Nuc. Acids Res. 28(20): 3982-3990 (2000)).
Immunotherapy, or the use of antibodies for therapeutic purposes has been used in recent years to treat cancer. Passive immunotherapy involves the use of monoclonal antibodies in cancer treatments. See for example, Cancer: Principles and Practice of Oncology, 6th Edition (2001) Ch. 20 pp. 495-508. Inherent therapeutic biological activity of these antibodies include direct inhibition of tumor cell growth or survival, and the ability to recruit the natural cell killing activity of the body's immune system. These agents are administered alone or in conjunction with radiation or chemotherapeutic agents. Rituxan® and Herceptin®, approved for treatment of lymphoma and breast cancer, respectively, are two examples of such therapeutics. Alternatively, antibodies are used to make antibody conjugates where the antibody is linked to a toxic agent and directs that agent to the tumor by specifically binding to the tumor. Mylotarg® is an example of an approved antibody conjugate used for the treatment of leukemia.
Accordingly, it is another object of this invention to provide antigens (cancer-associated polypeptides) associated with a variety of cancers as targets for diagnostic and/or therapeutic antibodies. These antigens are also useful for drug discovery (e.g., small molecules) and for further characterization of cellular regulation, growth, and differentiation.